Development of Novel In Vitro Models for Hepatitis B Virus and Hepatitis C Virus Infection and Replication

B型肝炎病毒（HBV）和C型肝炎病毒（HCV）是嗜肝病毒，感染后可引起肝脏的急、慢性疾病。全世界约有20亿人感染HBV。其中约3.5亿人患有慢性B型肝炎，每年死亡人数超过60万人（Ganem and Prince，2004）。据估计，全球HCV感染人数超过1.7亿，每年有超过350，000人死于HCV相关肝病（Te和詹森，2010）。尽管已经开发了抗HBV和抗HCV药物来治疗患者，但HBV或HCV难以完全根除。此外，长期药物方案对患者和医疗保健提供者都是昂贵的。因此，慢性HBV或HCV感染是导致发病和死亡的主要原因，对病毒感染、复制的深入研究是医学上的一个重要需求，这将有助于开发更有效的药物。对HBV或HCV感染和生命周期的详细研究一直受到人类金标准模型原代人肝细胞（PHH）来源和培养困难的阻碍。PHH是从低质量组织碎片中分离的稀缺资源，并且在有限的体外培养时间（2-4天）后丧失功能。因此，已经寻求并开发了替代模型。动物肝细胞、HCC细胞系或转基因小鼠模型有助于理解HBV和HCV的发病机制。然而，尽管它们取得了成功，但在这些模型中存在许多缺点，因此它们不能正确地模拟体内情况。所提出的项目将检查肝细胞的替代和可再生来源，其具有克服先前限制的潜力，并且在未来可以提供筛选治疗HBV和HCV感染个体的新药的平台。参考文献：Ganem D和Prince AM（2004）N Engl J Med，350，1118- 1129. Te HS和詹森DM（2010）Clin Liver Dis，14，1-21，vii.

Hepatitis B virus (HBV) and Hepatitis C virus (HCV) are hepatotropic viruses that can cause acute and chronic diseases in liver after infection. Up to 2 billion people have been infected by HBV in the world. Among those approximately 350 million of people have developed chronic Hepatitis B and the annual death is greater than 600,000 (Ganem and Prince, 2004). Global HCV infection has been estimated to be in excess of 170 million individuals, with more than 350,000 deaths per annum due to HCV-related liver disease (Te and Jensen, 2010). Although anti-HBV and anti-HCV drugs have been developed to treat patients, HBV or HCV are hard to completely eradicate. In addition, long-term drug regimes are expensive to both patients and healthcare providers. Chronic HBV or HCV infection is therefore a major cause of morbidity and mortality and major medical requirement exists to develop a better understanding of viral infection, replication which will lead to the development of more effective medicines.Detailed research on HBV or HCV infection and lifecycle has been hampered by difficulties in sourcing and culturing the human gold standard model, primary human hepatocytes (PHHs). PHHs are a scarce resource that are isolated from low quality tissue fragment and lose function following limited period of in vitro culture (2-4 days). Therefore, alternative models have been sought and developed. Animal hepatocytes, HCC cell lines, or transgenic mouse models have contributed to understanding the pathogenesis of HBV and HCV. However, despite their successes there are a number of shortcomings in those models and as a consequence they do not properly model the in vivo situation. The project proposed will examine an alternative and renewable source of hepatocytes which have the potential to overcome previous limitations, and in the future may offer a platform to screen for novel medicines to treat HBV and HCV infected individuals.References:Ganem D and Prince AM (2004) N Engl J Med, 350, 1118-1129.Te HS and Jensen DM (2010) Clin Liver Dis, 14, 1-21, vii.